Certain chemical entities, compositions and methods
Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
1. A compound of the formula
or a pharmaceutically acceptable salt thereof,
where one of Z 1 and Z 2 is —NR 15 C(O)NR 16 R 4 and the other of Z 1 and Z 2 is R 3 ;
R 4 is optionally substituted heteroaryl;
R 3 is chosen from hydrogen, halo, cyano, hydroxyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
R 1 and R 2 are independently chosen from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
R 15 and R 16 are independently chosen from hydrogen, and optionally substituted alkyl;
R 5 is optionally substituted piperazinyl; and
L is lower alkylene.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is chosen from 4-(dimethylcarbamoyl)piperazine-1-yl, 4-(N,N-dimethylsulfamoyl)piperazine-1-yl, 4-acetyl-piperazin-1-yl, 4-ethoxycarbonyl-piperazin-1-yl, 4-ethylsulfonyl-piperazin-1-yl, 4-methoxycarbonyl-piperazin-1-yl, 4-methylsulfonyl-piperazin-1-yl, 4-t-butoxycarbonyl-piperazin-1-yl, piperazin-1-yl, 4-(4-acetylpiperazine-1, carbonyl)piperazin-1-yl, 4-(4-methylpiperazine-1-carbonyl)piperazin-1-yl, 4-(piperidine-1-carbonyl)piperazin-1-yl, 4-(morpholine-4-carbonyl)piperazin-1-yl, 4-(cyclobutylsulfonyl)-piperazin-1-yl, 4-(ethylsulfonyl)piperazin-1-yl, 4-(isopropylsulfonyl)piperazin-1-yl, 4-(cyclopropylsulfonyl)piperazin-1-yl, and 4-(1,1-dioxide thiomorpholine-4-carbonyl)piperazin-1-yl.
3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is chosen from optionally substituted pyridinyl.
4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 4 is chosen from 6-methoxy-pyridin-3-yl, 6-methyl-pyridin-3-yl and pyridin-3-yl.
5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is chosen from hydrogen, halo, cyano, lower alkyl, and hydroxyl.
6. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is chosen from hydrogen, fluoro, chloro, methyl, ethyl and hydroxyl.
7. A compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently chosen from hydrogen, halo, cyano and lower alkyl.
8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof where R 1 , R 2 and R 3 are hydrogen.
9. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or adjuvant and at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.